1. Field of the Invention
The present invention relates, in general, to prodrugs. In particular, the present invention relates to lipophilic anti-viral and anticancer nucleoside prodrugs activated by endogenous aminohydrolase enzymes.
2. Background Information
Nucleoside analogues are currently used as the primary mode of drug treatment for almost all viral diseases caused by human immunodeficiency virus (HIV) and the herpes virus family (herpes simplex I and II, varicella-zoster, cytomegalovirus, Epstein-Barr). This class of compounds is also useful for treating certain types of cancer. HIV causes AIDS, while the various members of the herpes family cause a range of problems (cancer, genital warts, shingles, herpes encephalitis). Many of these afflictions are fatal if not successfully treated. When the causative agent (virus or cancer cell) spreads to a sanctuary in the body (central nervous system (CNS), testes, eye, etc), drug treatment is often difficult because conventional active drugs have difficulty reaching the target organ site. Prodrugs designed to overcome these transport problems, especially to the CNS, and then be activated by endogenous aminohydrolases to active drugs, are described here.
Acquired immune deficiency syndrome, or AIDS, is a fatal disease which has reached epidemic proportions among certain high risk groups. Several features of AIDS make therapy extremely difficult. The main target of the AIDS virus, now known as HIV, or human immunodeficiency virus, is the T4 lymphocyte, a white blood cell that marshals the immune defenses. This depletion of T4 cells in AIDS causes a severe depression of the immune response, so that a compound which is to be effective against AIDS must modify virus effect without much help from host immunity. Furthermore, the virus also affects cells in the central nervous system (Berger, J. R. & Resnick, L. in AIDS. Modern Concepts and Therapeutic Challenges, Broder, S., Ed., M. Dekker, N. Y., 1987, pp 263-283; Snider, W. D. et al. Ann Neurol. 1983, 14, 403; Fauci, A. S. Science 1988, 239, 617; Price, R. W. et al; Science 1988, 239, 586; Lane, H. C. & Fauci, A. S. in AIDS. Modern Concepts and Therapeutic Challenges, Broder, S., Ed., M. Dekker, N.Y., 1987, pp 185-203), where it is protected by the blood-brain barrier from compounds that might otherwise be effective against the virus (Mitsuya, Ho & Broder, S. Nature 1987, 325, 773; De Clercq, E. J. Med. Chem. 1986, 29, 1561; Mitsuya, H. & Broder, S. Proc. Nat. Acad. Sci. USA 1986, 83, 1911). In infecting its host, the HIV binds to specific cell-surface receptor molecules. The virus penetrates the cell cytoplasm and sheds its protein coat, thereby baring its genetic material, a single strand of RNA. A viral enzyme, reverse transcriptase, accompanies the RNA. The virus, which is a retrovirus, reverse transcribes the RNA into DNA. Ultimately, some DNA copies of the HIV genome become integrated into the chromosomes of the host cell.
This integrated viral genome, known as a provirus, may remain latent until the host cell is stimulated, such as by another infection. The proviral DNA is then transcribed into mRNA, which directs the synthesis of viral proteins. The provirus also gives rise to other RNA copies that will serve as the genetic material of viral progeny. The proteins and the genomic RNA congregate at the cell membrane and assemble to form new HIV particles, which then break off from the cell. Two HIV genes, tat and trs/art, appear to control this burst of replication, which destroys the cell. These genes code for small proteins that boost the transcription of proviral DNA and the synthesis of viral proteins.
Several compounds have been shown to reduce the activity of reverse transcriptase in vitro. The reverse transcription is the step that is essential to viral replication and irrelevant to host cells. It has been found that HIV replication is considerably slower in the presence of compounds such as suramin, antimoniotungstate, phosphonoformate, and a class of nucleoside analogues known as dideoxynucleosides (ddN).
Nucleoside analogues are a class of synthetic compounds that resemble the naturally occurring nucleosides, which are chemical precursors of DNA and RNA. A nucleoside comprises a single-or double-ring base linked to a five-carbon sugar molecule. An analogue differs from the naturally-occurring nucleoside in large or small features of the base or the sugar. An enzyme that normally acts on a nucleoside in the course of viral replication may also bind to the nucleoside analogue. Because the nucleoside and the analogue differ, however, binding to the analogue can incapacitate the enzymes, thereby disrupting a molecular process crucial to viral replication.
Of the synthetic nucleoside analogues, dideoxyadenosine (ddA), dideoxyinosine (ddI) and dideoxycytidine (ddC), have been found to have potent in vitro activity against the human immunodeficiency virus (HIV) which causes AIDS. Additionally, dideoxycytidine has been found effective in vivo in treating patients with AIDS, and dideoxyinosine and dideoxyadenosine are currently being tested in vivo in patients with AIDS.
The blood-brain-barrier protects the brain from potentially harmful materials in the systemic circulation. Unfortunately, this phenomenon can also exclude useful drugs. (Greig, N. Cancer Treat. Rev. 1987, 14, 1) Lipophilic, non-ionic, low molecular weight materials generally appear to have the best passive diffusion properties for CNS penetration. (Rall, D. P. & Zubrod, C. G. Annu. Rev. Pharmacol. 1962, 2, 109) It also has been reported that an active transport mechanism may play a role in BBB penetration of some nucleosides (Collins, J. M. et al. J. Pharmacol. Exp. Ther. 1988, 245, 466; Conford, E. M. & Oldendorf, W. H. Biochem. Biophys. Acta 1975, 394, 211) although the structural requirements necessary to make use of this possibility are not well defined.
In an attempt to provide new antiviral and anticancer drugs by enhancing in vivo transport properties in general, and CNS transport properties in particular, the present invention specifically provides purine and pyrimidine nucleoside prodrugs. These compounds, because of their lipophilic, biologically stable character, can be transported after administration to disease-site sanctuaries and then converted by endogenous aminohydrolases to active anti-HIV, anti-herpes or anticancer drugs. It has been found that adenosine deaminase can convert certain 6-substituted purine dideoxynucleoside prodrugs into antiretroviral (eg. HIV) active inosine and guanosine compounds. This general concept is also valid for prodrugs of certain other nucleosides and their analogues, including acyclic, purine-containing nucleosides which are antivirally active. The conversion of certain 4-substituted pyrimidin-2-one nucleoside prodrugs by cytidine deaminase to antiretroviral, antiviral and anticancer compounds is also possible. The prodrugs proposed, because of their need to be activated by an aminohydrolase, are, by definition, prodrugs of active inosine, guanosine, uridine, and thymidine analogues.